ABSTRACT The proposed study will examine the chronic hypertensive left ventricular hypertrophy subset of heart failure with preserved ejection fraction (HFpEF) to connect skeletal muscle ultrastructure and biochemistry to symptoms, quality of life, and functional capacity. Conditions including hypertension, sedentary lifestyle, muscular deconditioning, and obesity result in a variety of cellular changes, such as cardiac hypertrophy, neurohormonal dysregulation and derangements in protein homeostasis. These processes result in the development of HFpEF with the downstream sequelae of dyspnea and fatigue, decreased functional capacity, and structural muscle damage. Hypertension is one of the greatest contributors to cardiac-related mortality and is a primary cause of HFpEF as a result of left ventricular hypertrophy. This study hypothesizes that that heart failure (HF) symptoms and functional capacity are connected to skeletal muscle ultrastructure and biochemistry in persons with heart failure with preserved ejection fraction (HFpEF). This 2-year cross-sectional study will enroll 40 participants with HFpEF and use stored samples from healthy controls to examine skeletal muscle structure and function. Patient questionnaires will be used to assess fatigue, dyspnea severity and quality of life in persons with HFpEF. In addition, perceived barriers to and benefits of exercise will be assessed via questionnaire. Functional status will be assessed using the six-minute walk test and an exercise treadmill test. Muscle biopsies will be performed to study structural and functional aspects of skeletal muscle that determine functional capacity including the conventional assessment of quantification of fiber types, cross- sectional area, capillary density, and mitochondrial function, and to further explore a novel finding that examines a putative mechanism of myocyte ultrastructural damage, chymase-induced breakdown of desmin and mitochondrial dysfunction, as an important factor of functional capacity in persons with HFpEF. By focusing on a subset of patients with well-defined hypertension and left ventricular hypertrophy, data from this study can be used to create precision medicine in HFpEF prevention and treatment, targeted therapies, and better prediction of outcomes in this high mortality population.